NAC for Treatment of Oxidative Stress in Chronic Fatigue Syndrome

描述(申请人提供)：申请人最近进行的活体质子磁共振波谱(1HMRS)研究证明，活组织中最丰富和最重要的抗氧化剂谷胱甘肽(GSH)的平均皮质水平下降了36%。 慢性疲劳综合征(CFS)患者与健康对照组比较。这一发现，以及先前关于CFS氧化损伤血液标记物增加的可靠报告，强烈表明氧化应激增加与疾病的病理生理有关，并表明基于恢复皮质GSH水平以使氧化应激正常化的治疗策略的可行性。然而，由于GSH对血脑屏障(BBB)的渗透性差，直接补充GSH在提高皮质抗氧化剂水平方面并不可行。 包括神经元在内的大多数细胞的细胞膜。另一方面，由于半胱氨酸-一种具有良好的血脑屏障和膜转运特性的常见氨基酸-在GSH合成途径中的生物利用度是有限的，因此人们对这种氨基酸的无毒衍生物N-乙酰半胱氨酸(NAC)进行研究，作为一种合成前体，可以通过饮食手段来刺激脑GSH的原位升高。这些考虑表明了目前探索性/发展性(R21)项目的主要目标是：(A)调查每天补充2000 mg NAC是否会使15名CFS患者的1HMRS活体测量的皮质GSH升高，与15名匹配的健康对照组相比，并达到基线水平；(B)根据所有参与者体液样本中已建立的氧化应激标志物水平的变化，确定NAC引起的GSH升高是否会使CFS的氧化应激“正常化”；以及(C)探讨皮质GSH和氧化应激标志物水平的正常化是否与CFS症状的改善有关。如果成功，这项研究有可能(I)提供更多证据支持CFS新出现的氧化应激模型，(Ii)确定补充NAC是否导致体内皮质GSH升高，以及(Iii)提供初步证据，说明干预是否改善CFS症状，这将证明对NAC或其他GSH前体作为潜在的CFS神经保护治疗的更大规模研究是合理的。 与公共卫生相关：最近的研究发现，慢性疲劳综合征(CFS)患者体内主要组织抗氧化剂谷胱甘肽(GSH)水平显著下降，氧化剂损伤标志物水平上升，这表明在疾病的病理生理学中，氧化应激增加，从而为这项探索性/发展性(R21)研究提供了令人信服的理由，以评估(A)与15名匹配的对照受试者和基线相比，4周的每日补充2000 mg GSH合成前体N-乙酰半胱氨酸(NAC)是否会使皮质GSH正常化，通过质子磁共振波谱(1HMRS)在体内直接测量；(B)GSH正常化是否也会使CFS的氧化应激正常化，这是通过体液中已建立的氧化损伤标志物的水平来评估的；及(C)正常化皮质GSH和氧化应激是否会改善CFS的症状。如果成功，这项研究可能会为支持CFS新出现的氧化应激模型提供进一步的证据；确定补充NAC是否会提高体内皮质GSH并降低氧化应激；并为在更大规模的研究中进一步研究NAC或其他GSH前体作为CFS的潜在神经保护治疗提供令人信服的理由--目前这是一个难以捉摸和未得到满足的需求。

DESCRIPTION (provided by applicant): A recent in vivo proton magnetic resonance spectroscopy (1H MRS) study by the applicants has documented a 36% decrease in mean cortical levels of glutathione (GSH), the most abundant and important antioxidant in living tissue, in chronic fatigue syndrome (CFS) compared to healthy control subjects. This finding, along with prior credible reports of increased blood markers of oxidant damage in CFS, strongly implicates increased oxidative stress in the pathophysiology of the disorder, and suggests the viability of treatment strategies based on restoring cortical GSH levels to normalize oxidative stress. However, direct dietary supplementation of GSH has not proved viable in increasing cortical levels of the antioxidant due to its poor permeability through the blood-brain barrier (BBB) or the membranes of most cells, including neurons. On the other hand, since the bioavailability of cysteine - a common amino acid with favorable BBB and membrane transport properties - is rate-limiting in the GSH synthesis pathway, there is a great deal of interest in investigating the non-toxic derivative of this amino acid, N-acetylcysteine (NAC), as a synthetic precursor that can be supplied through dietary means to spur in situ elevation of brain GSH. These considerations suggested the main objectives of the present Exploratory/Developmental (R21) project, which are: (a) to investigate whether 4 weeks of daily supplementation with 2000mg of NAC will elevate cortical GSH, as measured in vivo by 1H MRS, in 15 patients with CFS compared to 15 matched healthy control subjects and to baseline; (b) to determine whether GSH elevations due to NAC, if any, would "normalize" oxidative stress in CFS, as assessed by changes in the levels of established makers of oxidative stress in body fluid samples from all participants; and (c) to explore whether normalization of levels of cortical GSH and oxidative stress markers will be associated with amelioration of CFS symptoms. If successful, this study has the potential to (i) contribute further evidence in support of the emerging oxidative stress model of CFS, (ii) to establish whether NAC supplementation leads to in vivo elevations of cortical GSH, and (iii) to provide preliminary evidence on whether the intervention ameliorates CFS symptoms, which would justify larger studies of NAC or other GSH precursors as potential neuroprotective treatments for CFS. PUBLIC HEALTH RELEVANCE: Recent findings of robust decreases in the levels of the primary tissue antioxidant, glutathione (GSH), and of increased levels of markers of oxidant damage in patients with chronic fatigue syndrome (CFS), have implicated increased oxidative stress in the pathophysiology of the disorder, thereby providing a compelling justification for thi Exploratory/Developmental (R21) research to assess (a) whether 4 weeks of daily supplementation with 2000mg of the GSH synthetic precursor N-acetylcysteine (NAC) would normalize cortical GSH, as measured directly in vivo by proton magnetic resonance spectroscopy (1H MRS) in 15 patients with CFS compared to 15 matching control subjects and to baseline; (b) whether normalization of GSH would also normalize oxidative stress in CFS, as assessed by levels of established oxidative damage markers in body fluids; and (c) whether normalizing cortical GSH and oxidative stress improves CFS symptoms. If successful, this research could potentially contribute further evidence in support of the emerging oxidative stress model of CFS; establish whether NAC supplementation elevates in vivo cortical GSH and decreases oxidative stress; and provide a compelling rationale to further investigate NAC or other GSH precursors in larger studies as potential neuroprotective treatments for CFS - currently an elusive and unmet need.